The hypothesis for this proposal is that the sodium hydrogen exchanger (NHE) plays two roles in the progression of Human non-small cell lung cancer. The first role is to coordinate the movement of proteins in and out of lipid rafts found at the leading edge of cells. One of these proteins, critical to invasion and metastasis process is MMP-9. The second role of NHE is the acidification of the microenvironment located at the leading edge of a migrating tumor cell. Both of these processes are important for the activation of MMP-9 and regulation of lung cancer invasion and metastasis. This proposal will test this hypothesis by creating a set of novel human lung cancer cell lines that are devoid of NHE. Mutant NHE constructs that are unable to transport protons or bind to the cytoskeleton will be expressed in these NHE-null cell lines. Then the effect of NHE on cell invasion and metastasis will be investigated along with studies determining the role of NHE on MMP-9 activation. The proposal will finish with a series of in vivo experiments using the tools and results of the prior aim to determine if NHE inhibitors can be used alone or in combination with other drugs as an effective therapeutic agent to fight aggressive non-small cell lung cancer. This proposal will fund the work of several students, giving them a meaningful research experience and will support the work of two professors at a primarily undergraduate university. PUBLIC HEALTH RELEVANCE: This project will provide new tools to understand how cancer cells move, and how a protein called the sodium hydrogen exchanger is important in cancer cell invasion. The project will investigate if an old approved drug for blood pressure might help fight one of the very aggressive cancers, non-small cell lung cancer. In addition, this work will provide resources and an opportunity for many college students to experience meaningful research on an important project [unreadable] [unreadable] [unreadable]